Methods and compositions for improved non-viral gene therapy

Abstract

Methods to prevent or reduce inflammation secondary to administration of a lipid-nucleic acid complex in a subject, that include administering to the subject a non-steroidal anti-inflammatory agent, a salicylate, an anti-rheumatic agent, an antihistamine, or an immunsuppressive agent with the lipid-nucleic acid complex are disclosed. Also disclosed are methods of screening for inhibitors of the inflammatory response associated with administration of a lipid-nucleic acid complex to a subject, including providing a candidate substance suspected of preventing or inhibiting the inflammation associated with administration of a lipid-nucleic acid complex to the subject. Also disclosed are compositions that include a lipid, a nucleic acid, and a non-steroidal anti-inflammatory agent, a salicylate, an anti-rheumatic agent, an antihistamine, or an immunosuppressive agent.

Description

[0001] This application claims the benefit of the filing date of U.S. provisional patent application Ser. No. 60 / 533,180, filed Dec. 30, 2003, the entire contents of which is hereby incorporated by reference.BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] The present invention relates generally to the fields of molecular biology and pharmacology. More particularly, it concerns methods to prevent or reduce inflammation secondary to administration of a lipid-nucleic acid complex in a subject, involving administering to the subject a non-steroidal anti-inflammatory agent, a salicylate, an anti-rheumatic agent, an antihistamine, or an immunosuppressive agent with the lipid-nucleic acid complex. The present invention also concerns methods of screening for inhibitors of the inflammatory response association with administration of a lipid-nucleic acid complex to a subject. In addition, the present invention concerns compositions that include a lipid, a nucleic acid, and...

AI Technical Summary

Benefits of technology

[0019] The inventors have discovered that anti-inflammatory drugs provide protection against the toxicity associated with administration of lipid-nucleic acid complexes. The inventors discovered that this protection is the result of downregulation of NF-κB, a potent stimulator of inflammation. These findings indicate that anti-inflammatory drugs (such as non-steroidal anti-inflammatory agents, salicylates, anti-rheumatic agents, antihistamines, immunosuppressive agents, and related agents) can protect against the toxicity associated with administration of lipid-nucleic acid complexes.

Problems solved by technology

However, viral vectors are limited by (1) their relatively small capacity for therapeutic DNA, (2) safety concerns, and (3) difficulty in targeting to specific cell types.

These difficulties have led to the evaluation and development of alternative vectors based on synthetic, non-viral systems.

Problems with the efficiency of nucleic acid encapsulation, coupled with a requirement to separate the DNA-liposome complexes from “ghost” vesicles, has led to the development of positively-charged liposomes.

Although many cell culture studies have documented lipid-based non-viral gene transfer, systemic gene delivery via lipid-based formulations has been limited.

A major limitation of non-viral lipid-based gene delivery is the toxicity of the cationic lipids that comprise the non-viral delivery vehicle.

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